Pharmaceutical tablet system that floats on gastric fluid for multipulse release of active substance and respective processes of producing same and a cup-shaped envelope of same

ABSTRACT

A tablet system for prolonged floating in or on gastric fluid for releasing therein pharmaceutically active substances in an alternate succession of substance release and no-release periods is made up of a multilayered core placed in a cup-shaped envelope. The core is made up of release layers and no-release layers devoid of pharmaceutically active substance, superposed in alternate succession. The cup-shaped envelope covers bottom and side surfaces of the core while leaving exposed an upper surface of the core. The cup-shaped envelope provides for buoyancy by being formed of a compression-sintered mixture comprising hydrophobic material and inert powdered filler. The hydrophobic material is composed of fatty and/or waxy material capable of being sintered by compression and whose bulk density is lower than gastric fluid density. The powdered filler has a loose powder density that is lower than gastric fluid density.

TECHNICAL FIELD OF THE INVENTION

[0001] This invention concerns a pharmaceutical tablet system capable ofprolonged floating in or on gastric fluid for releasing therein one ormore pharmaceutically active substances in the course of an alternatesuccession of periods of substance release and no-release, saidalternate succession including at least two periods of substance releaseseparated by one period of no-release i.e. of latency. This inventionalso concerns a process of producing said pharmaceutical tablet systemand a process of producing a cup-shaped envelope of said pharmaceuticaltablet system.

BACKGROUND ART

[0002] For an overall view of the field of the art to which theinvention pertains, reference may be made for instance to Moës A. J.,“Gastroretentive Dosage Forms”, Critical Reviews in Therapeutic DrugCarrier Systems 10(2):143-195 (1993), and also to Singh B. N. et al.,“Floating drug delivery systems: an approach to oral controlled drugdelivery via gastric retention”, Journal of Controlled Release63(3):35-259 (2000).

[0003] Pharmaceutical tablet systems capable of prolonged floating in oron gastric fluid e.g. so as to have a long time of residence in apatient's stomach for releasing therein a pharmaceutically activesubstance in sustained manner are known in the art. Generally,pharmaceutical forms having a long time of residence in a patient'sstomach are of great interest, not only because they allow a localtreatment of the patient's stomach wall and more particularly of thegastric mucous membrane, but also and above all because they allow torelease active substance in the vicinity of the patient's duodenum,which is a very favourable location of the gastro-intestinal tract wherea great many active substances are best absorbed.

[0004] There are several approaches for bringing about a prolonged timeof residence in the stomach.

[0005] A tablet system can be formulated so as to adhere to the gastricmucous membrane (cf. for instance U.S. Pat. No. 5,213,794, U.S. Pat. No.5,571,533, WO-A-93/24124, WO-A-98/42311, WO-A-98/52547). A majordrawback of such adhering systems resides in the difficulty of bringingabout that they reliably adhere and remain adherent to the gastricmucous membrane, for the latter is continually undergoing changes andreplacement processes and is also subject to the peristalsis i.e. tostrong contractions that take place at the stomach wall. In respect ofadherence to the gastric mucous membrane no helpful knowledge can bederived from currently used pharmaceutical forms designed to adhere e.g.onto nasal or buccal surfaces, because such forms need to be pressedonto said surfaces at application time, which pressing is not possibleonto a patient's gastric mucous membrane, to say nothing of the hazardof the forms getting stuck in the patient's esophagus.

[0006] A tablet system can also be formulated to have a high apparentdensity that, following ingestion, will cause the system to settle inthe stomach at the lower portion of the antrum (cf. for instance U.S.Pat. No. 4,193,985, U.S. Pat. No. 5,374,430). However, the movement ofsubstances contained in the stomach towards the lower portion of theantrum participates in the natural sequence of events related to gastricdischarge and hence, pharmaceutical forms formulated so as to settle inthe antrum are likely to pass the patient's pylorus either with thebolus (during the digestion process) or together with undigested debris(in the time interval between two successive digestion processes). Thus,to secure the gastroretention of systems formulated so as to have a highapparent density, such systems must additionally be given someproperties that will promote the gastroretention, which will raise againthe problems already discussed above. Indeed, in EP-A-526862 a granulateis disclosed that not only has a high density but also is givenmuco-adhesive properties.

[0007] A tablet system can also be formulated so as to grow in thestomach, following ingestion, to a size large enough to hinder thesystem from passing the patient's pylorus even when the latter is open.A great many of these systems are either folded at ingestion time andmade to unfold and open out in the stomach following ingestion (cf. forinstance EP-A-202159, U.S. Pat. No. 4,735,804, U.S. Pat. No. 4,758,436,U.S. Pat. No. 4,767,627, U.S. Pat. No. 5,002,772) or they are made toswell in the stomach following ingestion, for example as a result ofgelling (cf. for instance U.S. Pat. No. 4,434,153, U.S. Pat. No.5,651,985) or carbon dioxide emission (cf. for instance U.S. Pat. No.4,996,058, WO-A-98/31341). However, systems formulated to swell couldeasily pass the patient's pylorus during the latency period that runsfrom ingestion time until the system has grown to a sufficient size forthe gastroretention mechanism to become effective. On the other hand,systems formulated to unfold and open out in the stomach might well beretained permanently in the stomach or even in the esophagus, due toearly activation of the deployment mechanism. Each of such failure caseswill cause severe secondary effects.

[0008] A tablet system can also be formulated with agents that delay orslow down the transit through the stomach, such as lipid-based vehicles(for instance, fatty acids) or depressors of the central nervous system(for instance, serotonine antagonists). These agents bring about areduction of the stomach motility, which in turn slows down the gastricdischarge. Such a way of bringing about gastroretention is most oftenused in association with other ways (cf. for instance WO-A-97/47285).However, as systems that bring about a reduction of the stomach motilityinterfere with the whole mechanism of gastric discharge, they are likelyto cause digestion problems or worsen them, if already existing.Furthermore, the use of a serotonine antagonist has to comply withpertaining health and drug regulations.

[0009] Hence, all known tablet systems of the above mentioned types mustbe deemed unreliable in respect of providing a prolonged time ofresidence in the stomach and therefore, they all are unsuitable forproviding reliably an alternate succession of periods of substancerelease and no-release with at least two periods of substance releaseseparated by one period of no-release e.g. when structured in accordancewith the teaching of EP-A-788790.

[0010] A tablet system can also be formulated to float on the content ofthe stomach.

[0011] The buoyancy of such a tablet system may be provided by means ofan initially dense matrix that undergoes gelling in the stomachfollowing ingestion, which causes the matrix to swell and hence, reducesits density (cf. for instance GB-A-1546448, U.S. Pat. No. 4,126,672,U.S. Pat. No. 4,140,755, U.S. Pat. No. 4,167,558, U.S. Pat. No.5,169,639, U.S. Pat. No. 5,360,793, WO-A-96/29054); or the buoyancy ofsuch a tablet system may be provided by means of a film or coating thatundergoes carbon dioxide emission in the stomach following ingestion,which causes the film or coating to foam (an effect that may beunderstood as a special type of swelling) and hence, reduces its density(cf. for instance U.S. Pat. No. 4,101,650, U.S. Pat. No. 4,844,905,WO-A-98/47506); or the buoyancy of such a tablet system may be obtainedby providing it right from the start (i.e. before ingestion) with adensity that is sufficiently low to keep the tablet system floating inthe stomach following ingestion (cf. for instance JP-A-3-101615, U.S.Pat. No. 3,976,764, U.S. Pat. No. 4,702,918, U.S. Pat. No. 4,814,178,U.S. Pat. No. 4,814,179, U.S. Pat. No. 5,198,229, U.S. Pat. No.5,232,704, U.S. Pat. No. 5,288,506, U.S. Pat. No. 5,626,876).

[0012] Besides the fact that some of these tablet systems formulated tofloat on the content of the stomach may have their own severe drawbacks,all these systems (with the single exception of the above-mentioned U.S.Pat. No. 4,140,755) only bring about a single period of release ofactive substance (irrespective of the fact that the active substance mayactually consist of a mixture of active compounds). As to the systemdisclosed in the above-mentioned U.S. Pat. No. 4,140,755, this lattersystem can only bring about a single immediate release of activesubstance followed by a single prolonged release of the same activesubstance.

[0013] Thus, none of the above-mentioned tablet systems formulated tofloat on the content of the stomach is capable of providing reliably a“multipulse release” consisting of an alternate succession of periods ofsubstance release and no-release, which alternate succession wouldinclude at least two periods of substance release separated by oneperiod of no-release.

[0014] Yet, such a multipulse release capability is highly desirable ina tablet system formulated to float on the content of the stomach, forit would allow a patient to take one single drug unit form to produce adrug plasma level scheme that can only result at present times fromadministering to the patient two or more standard-type fast-release drugunit forms to be taken in succession at respective predefined timeinstants separated by respective predefined latency or waiting periods.

[0015] Pharmaceutical tablet systems having a multipulse releasecapability are known in the art.

[0016] One type of a pharmaceutical tablet system having a multipulserelease capability is known for instance from EP-A-1074249 and isconstructed as a multilayered body arranged concentric about a core,which core is fully enclosed within layers that fully enclose oneanother in succession. The core is the last part of the tablet systemthat will disappear by dissolution or digestion in gastric fluid or bygastric discharge and hence, to confer prolonged buoyancy to such atablet system and prevent any early sinking or discharge thereof, atleast the core should be formed of lightweight materials. Moreover, inconsideration of the possible gastric discharge of the core, a reliableadministration can only be attained with a core devoid of any activesubstance that participates in the desired multipulse releasecapability, which is not an economical construction because of thenecessarily large size of the core.

[0017] Another type of a pharmaceutical tablet system having amultipulse release capability is known for instance from WO-A-91/04015,EP-A-631775 or EP-A-788790 and is, basically, made up of planar layerssuperposed in a stack that is enclosed within an envelope so as to leaveat least one outer face of an outer layer of the stack uncovered andunprotected by the envelope. In particular, there is disclosed inEP-A-788790 a pharmaceutical tablet system to be administered by theoral route for releasing one or more pharmaceutically active substancesin the course of an alternate succession of periods of substance releaseand no-release, said alternate succession including at least two periodsof substance release separated by one period of no-release. This type ofpharmaceutical tablet system is neither intended nor provided forprolonged floating in or on gastric fluid in a patient's stomach.

[0018] To nevertheless confer buoyancy to this type of pharmaceuticaltablet system, it may be envisaged to use lightweight materials to formthe envelope, and this may be expected to be easiest in a tablet systemhaving a cup-shaped envelope and a multilayered core placed therein, asdisclosed in EP-A-788790. The cup-shaped envelope is the last part ofthe tablet system that will disappear by dissolution or digestion ingastric fluid or by gastric discharge and hence, to confer prolongedbuoyancy to such a tablet system and prevent any early sinking ordischarge thereof, at least the cup-shaped envelope should be formed oflightweight materials. Moreover, in consideration of the possiblegastric discharge of the cup-shaped envelope, a reliable multipulserelease can only be attained with a cup-shaped envelope devoid of anyactive substance that participates in the desired multipulse releasecapability.

[0019] Lightweight materials, the use of which may be envisaged inpharmaceutical tablet systems of the above-mentioned type having amultipulse release capability, are known e.g. from the prior artmentioned above. Also, fatty and/or waxy lightweight materials have beenused to obtain tablet systems having a low density, for instanceaccording to JP-A-1-016715 that discloses a system having a fatty coremade up of fats and oils of density _(—)0.98 and at least one coatinglayer that contains active substance.

[0020] However, these known lightweight materials will not withstand aprolonged floating in or on gastric fluid, as some will dissolve in thegastric fluid, which will cause a progressive loss of buoyancy andsubsequent gastric discharge of the tablet system, and others willexperience a change of volume e.g. due to gelling that in turn willentail changes of shape allowing the core to eventually become detachedfrom the cup-shaped envelope: in either case the multipulse releasecharacteristics will be unreliable. In a pharmaceutical tablet system ofthe type mentioned above made up of a stack of superposed layers that isenclosed within an envelope with an outer layer of the stack having anouter face left uncovered and unprotected by the envelope, any poorcontact and attachment between the stack of layers and the envelope willallow gastric fluid to infiltrate the system, causing fragility of thetablet system as well as undesirable variations more particularly of thein vivo release rate of the active substance from the innermost i.e.lowermost layer of the stack, producing the so-called “dose dumping”. Inthe particular tablet system having a cup-shaped envelope and amultilayered core placed therein (as disclosed in EP-A-788790) thecaused fragility of the tablet system may even allow the core to detachfrom the cup-shaped envelope.

[0021] Also, fats and oils that are currently used (alone or in mixture)in pharmaceutical tablet systems to confer them a density that is lowerthan unity do not allow tablet production using a compression step ofthe kind performed in any currently used type of tablet compressionapparatus, because of feeding and sticking problems: such fats and oils(whether taken as powders or liquids) have flow properties that do notallow to reliably and evenly fill the press moulds, and during thecompression step they stick to the moulding plug and die, impairing thecompression efficiency and uniformity.

SUMMARY OF THE INVENTION

[0022] Thus, it is an object of the present invention to make availablea pharmaceutical tablet system capable of prolonged floating in or ongastric fluid under conditions that are safe for a patient to whom saidpharmaceutical tablet system is being administered, for releasing in thepatient's stomach one or more pharmaceutically active substances in thecourse of an alternate succession of periods of substance release andno-release, said alternate succession including at least two periods ofsubstance release separated by one period of no-release i.e. of latency,and which pharmaceutical tablet system does not have the drawbacks ofthe floating systems of the prior art mentioned above and in particular,should remain floating in or on the gastric fluid in a patient's stomachuntil the totality of the active substance contained in thepharmaceutical tablet system has been released, irrespective of the factthat said active substance may actually consist of a mixture of activecompounds.

[0023] To attain this object, according to the present invention thereis provided a pharmaceutical tablet system capable of prolonged floatingin or on gastric fluid for releasing therein one or morepharmaceutically active substances in the course of an alternatesuccession of periods of substance release and no-release, saidalternate succession including at least two periods of substance releaseseparated by one period of no-release, whereby:

[0024] the tablet system is made up of a multilayered core placed in acup-shaped envelope;

[0025] the core is made up of release and no-release layers superposedin alternate succession to form a pile of layers that includes at leasttwo release layers flanking an intermediate no-release layer, eachrelease layer being composed of pharmaceutically acceptable excipientand/or carrier having admixed thereto at least one of saidpharmaceutically active substances, each no-release layer being composedof pharmaceutically acceptable excipient and/or carrier devoid of saidpharmaceutically active substance;

[0026] the cup-shaped envelope covers a bottom surface and side surfacesof the core placed therein while leaving exposed an upper surface of thecore;

[0027] the cup-shaped envelope provides for buoyancy of thepharmaceutical tablet system with respect to gastric fluid by beingformed of a compression-sintered mixture that comprises pharmaceuticallyacceptable hydrophobic material and pharmaceutically acceptable inertpowdered filler;

[0028] the hydrophobic material is composed of fatty and/or waxymaterial capable of being sintered by compression and whose bulk densityis lower than gastric fluid density; and

[0029] the powdered filler having a loose powder density that is lowerthan gastric fluid density.

[0030] Preferably, in a pharmaceutical tablet system according to thepresent invention the voids may be interstices between grains of thepowdered filler, and more preferably, may be generally sealed off fromeach other by virtue of the hydrophobic material. Also preferably, thevoids may be micropores included within the hydrophobic material. Alsopreferably, the mixture, which the cup-shaped envelope is made of, alsoincludes at least one or more pharmaceutically active agent differentfrom said substances contained in one or more release layers.

[0031] A process of producing the above-defined pharmaceutical tabletsystem involves the steps of coating the powdered filler with thehydrophobic material, preferably by spray-coating performed undervigorous stirring; granulating the resulting coated material; placing alayer of the resulting granulated material into a die; placing a coreonto the layer of granulated material within the die; forcing the coreinto the layer of granulated material within the die, which forcingpreferably involves a compression of the tablet system made up of thecup-shaped envelope having the core inserted therein to provide a snugfit between mutually facing bottom and side surfaces of the core andsurface portions of the cup-shaped envelope; and removing the resultingtablet system from the die.

[0032] A process of producing a cup-shaped envelope of the above-definedpharmaceutical tablet system involves the steps of coating the powderedfiller with the hydrophobic material, preferably by spray-coatingperformed under vigorous stirring; granulating the resulting coatedmaterial; placing a layer of the resulting granulated material into adie; forming a cup-shaped recess into the layer of granulated materialby forcing a correspondingly shaped body into it within the die; andremoving the resulting cup-shaped envelope from the die.

[0033] In the pharmaceutical tablet system of the present invention itis the cup-shaped envelope that provides for buoyancy with respect togastric fluid. The system is constructed to float on gastric fluid atleast until the core will have disappeared completely by dissolution ordigestion in the gastric fluid and/or subsequent gastric discharge,which also means that all of the active substance will have been fullyreleased. Accordingly, a pharmaceutical tablet system of the presentinvention will reliably bring about the desired “multipulse release”defined above, irrespective of the fact that the active substance mayactually consist of a mixture of active compounds, and irrespective ofthe duration of the release or no-release i.e. latency periods.

[0034] A great advantage of the pharmaceutical tablet system of thepresent invention is that it allows a patient to take one single drugunit form to reliably produce a drug plasma level scheme equivalent tothat which would result from the patient's taking in succession two ormore standard-type fast-release drug unit forms at respective predefinedtime instants separated by respective predefined no-release i.e. latencyor waiting periods.

[0035] It is particularly advantageous to produce the tablet system bymeans of the preferred process according to the present invention, whichprocess reliably allows to obtain a snug fit between mutually facingbottom and side surfaces of the core and surface portions of thecup-hasped envelope, which snug fit in turn prevents the core fromdetaching too early from the cup-shaped envelope and hence, allows thetablet system to provide reliably the desired “multipulse release”.

[0036] Moreover, the lightweight material used in the pharmaceuticaltablet system of the present invention is advantageously well adapted tobe compressed in currently used rotary or reciprocating presses withoutgiving rise to any sticking or feeding problems. This finding is quitesurprising in view of the difficulties (e.g. unreliable and irregularfilling of press moulds, sticking to the moulding plug, impairedcompression) that are encountered when fats and oils are used to obtaina low apparent density as taught in the prior art e.g. of JP-A-1-016715quoted above.

[0037] Also, inherent to producing the pharmaceutical tablet system ofthe present invention according to the above said process, thelightweight material may advantageously be imparted such appropriatehardness and friability properties that will allow an easy handling ofintermediate and final products during any subsequent operations such asfilm coating, packaging etc.

[0038] In the process of producing the pharmaceutical tablet system ofthe invention, the combined provision of using of a hydrophobic materialcomposed of fatty and/or waxy material capable of being sintered bycompression, using a powdered filler having a loose powder density thatis lower than gastric fluid density and compressing the cup-shapedenvelope having the core inserted therein is advantageous in that itresults in a snug fit between the core and the cup-shaped envelope. Thissnug fit seals off the core from the gastric fluid except for the outerface of the core and thus, precludes any poor contact and attachmentbetween the core and the cup-hasped envelope. As no gastric fluid isallowed to infiltrate along the interface between the core and thecup-shaped envelope, the risk of early dissolution or degradation of anyother portions of the core than the vicinity if its outer surface isavoided. Such early dissolution would make the no-release or latencyperiod unreliable and/or cause early release of active substance fromlower layers of the core, which in turn would lead e.g. to a sustainedrelease instead of a multipulse release of active substance from thepharmaceutical tablet system.

[0039] It is a further advantage of the pharmaceutical tablet system ofthe invention that the hydrophobic material composed of fatty and/orwaxy material is sintered by compression, not by melting. Both thedegree of sintering and the degree of penetration of the hydrophobicmaterial into the powdered filler can be varied by means of thesintering pressure used, which allows to vary the final properties ofthe cup-shaped envelope, including the latter's final porosity and thus,the overall porosity of the system.

[0040] It is a still further advantage of the pharmaceutical tabletsystem of the invention that its mechanisms that provide for release andno-release and for buoyancy are independent from each other. This isbecause no hydrocolloids are used to provide for buoyancy with respectto gastric fluid, the tablet system experiences no change of volume, itsbuoyancy is not obtained by any gelling of hydrocolloids, and the activesubstance may be released by other mechanisms that diffusion through agelled body, which latter mechanism usually leads to a sustainedrelease. All the more, hydrocolloids have a gelling speed that, in apatient's gastric fluid, depends on physiological circumstances such ason the patient's stress, the fluid quantity available in the stomach,the instant filling state of the stomach etc., and in the pharmaceuticaltablet system of the invention this is avoided.

BRIEF DESCRIPTION OF THE DRAWINGS

[0041]FIG. 1 illustrates an exemplary embodiment of a tablet systemaccording to the present invention with a cylindrical tablet viewed in aschematic axial section;

[0042]FIG. 2 illustrates in vitro release characteristics of a tabletsystem according to FIG. 1 with a composition according to Example 1.

[0043]FIG. 3 illustrates in vitro release characteristics of a tabletsystem according to FIG. 1 with a composition according to Example 2.

[0044]FIG. 4 illustrates in vitro release characteristics of a tabletsystem according to FIG. 1 with a composition according to Example 3.

DETAILED DESCRIPTION OF THE INVENTION

[0045] The present invention will now be explained in closer detail withreference to an exemplary structure of a pharmaceutical tablet system,which structure is of the kind generally known from EP-A-788790. Thisexemplary structure is constructed cylindrical, and an axial sectionthereof is illustrated schematically in FIG. 1.

[0046] Generally, the tablet structure illustrated in FIG. 1 comprises acore partially enclosed within an envelope made of lightweight materialthat provides for buoyancy of the pharmaceutical tablet system withrespect to gastric fluid e.g. in a patient's stomach. The core is madeup of of three planar layers that are superposed sandwich-like in agenerally cylindrical stack having a latency layer 2 locatedintermediate between active layers 1 and 3. Also, the core is snuglyenclosed within a cup-shaped envelope 4 that is generally shaped as ablin-dend hollow cylinder having an axial cylindrical cavity in whichthe core i.e. the stack of layers 1, 2 and 3 is snugly accommodated insuch manner that an outer face of the outer layer 1 of the stack remainsuncovered and unprotected by the envelope 4.

[0047] The active layers 1 and 3 each are designed to provide release ofone or more pharmaceutically active substances and thus, they eachcontain active substance that is, in the present description and by wayof example, diltiazem HCl. The latency layer 2 is designed devoid ofactive substance so as to provide a period of no-release i.e. oflatency.

EXAMPLE 1

[0048] 1. Preparation of Active Layers

[0049] Active layers i.e. layers containing active substance wereprepared, each having a weight of 62.50 mg and the following percentagecomposition (by weight): diltiazem HCl 30.00% lactose (lactose pulvisH20, 200 Mesh) 59.50% from Paul Brem AG, Switzerland sodiumcroscarmellose Ac-Di-Sol^((R)), 5.00% from FMC Corporation, USAPolyvinylpyrrolidone Plasdone^((R)) K29-32, 4.00% from ISP AG,Switzerland magnesium stearate from Merck, Germany 1.00% colloidalsilica Aerosil^((R)) 200, 0.50% from Degussa AG, Hanau, Germany Totalcomposition 100.00%

[0050] Granulate was prepared in an amount appropriate to allow theproduction of 12000 cores of the type described above i.e. of 24000active layers.

[0051] Proper amounts of Diltiazem HCl, lactose, sodium croscarmelloseand polyvinylpyrolidone were placed in a mixer (from Stephan,Switzerland) and mixed therein. Subsequently the homogeneous mixture waswetted with demineralised water and then further mixed, a process knownin the art as a “wet massing” step.

[0052] The paste so obtained was dried in a fluidised air bed drier(type Niro-Aeromatic Strea I, 60° C. inlet air temperature, fromAeromatic-Fielder AG, Switzerland). The resulting dried mass was thensized through a sieve granulator (type Frewitt GLA, from FrewittFabrique de Machines SA, Switzerland) with a sieve of 0.8 mm aperture,which step produced calibrated granulate.

[0053] This calibrated granulate was then placed in a cubic mixer (typeErweka, from Mapag Maschinen AG, Switzerland), added with a properamount of colloidal silica, and mixed for 15 min at 12 rpm. Then, aproper amount of magnesium stearate was added, and mixing was continuedfor 5 min. This mixture was then used for the compression step asdescribed below.

[0054] 2. Preparation of No-Release i.e. Latency Layers

[0055] Latency layers i.e. layers devoid of active substance wereprepared, each having a weight of 100.00 mg and the following percentagecomposition (by weight): dibasic calcium phosphate 45.00% fromEmcompress^((R)), Mendell, USA) lactose (lactose pulvis H20, 200 Mesh)20.00% Lactose Fast Flo^((R)), from Foremost, USA glyceryl behenateCompritol^((R)) 888 ATO, 25.00% from Gattefossé, Francepolyvinylpyrrolidone Plasdone^((R)) K29-32, 8.40% from ISP AG,Switzerland yellow ferric oxide Sicovit^((R)) Yellow 10E172, 0.10% fromBascom AG, Switzerland magnesium stearate from Merck, Germany 1.00%colloidal silica Aerosil^((R)) 200, 0.50% from Degussa AG, Hanau,Germany Total composition 100.00%

[0056] Granulate was prepared in an amount appropriate to allow theproduction of 15000 cores of the type described above i.e. of 15000latency layers.

[0057] Proper amounts of dibasic calcium phosphate, lactose, glycerylbehenate, polyvinylpyrolidone and yellow ferric oxide were placed in amixer (from Stephan, Switzerland) and mixed therein. The homogeneousmixture was then wetted with demineralised water and then further mixedin a “wet massing” step.

[0058] The paste so obtained was dried in a fluidised air bed drier(type Niro-Aeromatic Strea I, 50° C. inlet air temperature, fromAeromatic-Fielder AG, Switzerland). The resulting dried mass was thensized through a sieve granulator (type Frewitt GLA, from FrewittFabrique de Machines SA, Switzerland) with a sieve of 0.8 mm aperture,which step produced calibrated granulate.

[0059] This calibrated granulate was then placed in a cubic mixer (typeErweka, from Mapag Maschinen AG, Switzerland), added with a properamount of colloidal silica, and mixed for 15 min at 12 rpm. Then, aproper amount of magnesium stearate was added, and mixing was continuedfor 5 min. This mixture was then used for the compression step asdescribed below.

Preparation of Buoyant Material

[0060] Buoyant material was prepared, having the following percentagecomposition (by weight): hydrogenated castor oil Cutina HR^((R)), 70.00%from Impag AG, Switzerland magnesium aluminometasilicate NeusilinUFL^((R)), 12.25% from Gustav Parmentier, Germany microcrystallinecellulose Avicel^((R)) pH 101, 12.25% from Selectchemie AG, Switzerlandgelatine from Merck, Germany 5.00% magnesium stearate from Merck,Germany 0.50% Total composition 100.00%

[0061] In the above composition eventually used for preparing thecup-shaped envelope, cf. below, the hydrophobic material is hydrogenatedcastor oil and the inert powdered filler is magnesiumaluminometasilicate.

[0062] Granulate was prepared in an amount appropriate to allow theproduction of 1000 buoyant cup-shaped envelopes each having a weight of500.00 mg appropriate to enclose 1000 cores so as to manufacture 1000tablets.

[0063] Proper amounts of hydrogenated castor oil, magnesiumaluminometasilicate and cellulose microcrystalline were placed in a highshear mixer (type Niro-Fielder PP1, from Aeromatic-Fielder AG,Switzerland). The homogeneous mixture was then wetted with a gelatinesolution made up of gelatine previously dissolved in demineralised waterand then further mixed in a “wet massing” step.

[0064] The paste so obtained was dried in a fluidised air bed drier(type Niro-Aeromatic Strea I, 50° C. inlet air temperature, fromAeromatic-Fielder AG, Switzerland). The resulting dried mass was thensized through a sieve granulator (type Frewitt GLA, from FrewittFabrique de Machines SA, Switzerland) with a sieve of 0.8 mm aperture,which step produced calibrated granulate.

[0065] This calibrated granulate was then placed in a cubic mixer (typeErweka, from Mapag Maschinen AG, Switzerland), added with a properamount of colloidal silica, and mixed for 10 min at 12 rpm. This mixturewas then used for the compression step as described below.

Preparation of Cores

[0066] Cores were prepared by means of a rotating three layer press(type Manesty LP39, from Keyser Mackay, Switzerland) equipped withcircular convex punches having a diameter of 7.0 mm, operating on thegranulates prepared as described above with bulk active layer materialin the first and third filling hoppers and bulk latency layer materialin the second filling hopper.

[0067] Application of buoyancy conferring layers onto cores

[0068] The cores previously prepared as described above werepress-coated with the buoyant material prepared as described above bymeans of a single punch machine (type Korsch, from KorschMaschinenfabrik, Germany) equipped with dies and circular convex puncheshaving a diameter of 13.0 mm. The die was filled with an exact quantityof the buoyant material and then the core was placed manually in the dieand centred. Subsequently, the compression step was then performed.

[0069] The resulting tablets had a thickness of 7.10 mm and a hardnessof about 75N.

Results

[0070] To determine the in vitro release characteristics of the tabletsdescribed above, a standard equipment was used as defined and describedin United States Pharmacopoeia USP XXIII, chapter 711, page 1792,paragraph “Apparatus 2”. This equipment had a stirring paddle comprisedof a blade and a shaft and was operated at 100 rpm. Dissolution wasinvestigated at 37° C. in 600 ml of a dissolution medium made up of 0.1Macetate buffer of pH 4.5. The release of the active substance (diltiazemHCl) was monitored by UV spectrophotometry at 278 nm for 6 individualsamples and additionally, as a reference, for the dissolution mediumtaken alone i.e. devoid of any tablet material.

[0071] The results are illustrated in FIG. 2 as respective time profilediagrams for the 6 tablet samples and the reference. The referencediagram showed that the dissolution medium taken alone i.e. devoid ofany tablet material did not bias the results or generate any artifacts.The in vitro release characteristics of all 6 tablets appeared to form awell grouped family that was well separated from the referencecharacteristic which appeared in the lowest part of the diagram.

[0072] In each instance, the following was observed on the in vitrorelease characteristics:

[0073] The first release of active substance takes place within arelease period of less than a one hour duration.

[0074] The no-release period appears as a well-defined time intervalobserved between the end of the first release and the start of thesecond release, having a duration of more than 8 hours in each instance.

[0075] The second release of active substance is observed to produce acontrolled release.

[0076] During the course of the dissolution the tablet system wasmonitored visually and observed to remain buoyant for the whole durationof the experiment.

EXAMPLE 2

[0077] 1. Preparation of Active Layers

[0078] Active layers i.e. layers containing active substance wereprepared, each having a weight of 62.50 mg and the following percentagecomposition (by weight): diltiazem HCl 30.00% lactose (lactose pulvisH20, 200 Mesh) 34.50% from Paul Brem AG, Switzerland sodiumcroscarmellose Ac-Di-Sol^((R)), 5.00% from FMC Corporation, USA sodiumhydrogen carbonate 15.00% from CFS, Switzerland polyvinylpyrrolidonePlasdone^((R)) K29-32, 4.00% from ISP AG, Switzerland citric acid fromMerck, Germany 10.00% magnesium stearate from Merck, Germany 1.00%colloidal silica Aerosil^((R)) 200, 0.50% from Degussa AG, Hanau,Germany Total composition 100.00%

[0079] Granulate was prepared in an amount appropriate to allow theproduction of 11000 cores of the type described above i.e. of 22000active layers, using the same procedure as described above under Example1 applied to proper amounts, first of diltiazem HCl, lactose, sodiumcroscarmellose, sodium hydrogen carbonate and polyvinylpyrolidone, andthen of colloidal silica and citric acid, placed in the respectivemixer.

Preparation of No-Release i.e. Latency Layers

[0080] Latency layers i.e. layers devoid of active substance wereprepared, each having a weight of 70.00 mg and the following percentagecomposition (by weight): dibasic calcium phosphate 37.50% fromEmcompress^((R)), Mendell, USA) lactose (lactose pulvis H20, 200 Mesh)33.34% Lactose Fast Flo^((R)), from Foremost, USA glyceryl behenateCompritol^((R)) 888 ATO, 20.83% from Gattefossé, Francepolyvinylpyrrolidone Plasdone^((R)) K29-32, 7.00% from ISP AG,Switzerland yellow ferric oxide Sicovit^((R)) Yellow 10E172, 0.08% fromBascom AG, Switzerland magnesium stearate from Merck, Germany 0.83%colloidal silica Aerosil^((R))200, 0.42% from Degussa AG, Hanau, GermanyTotal composition 100.00%

[0081] Granulate was prepared in an amount appropriate to allow theproduction of 2150 cores of the type described above i.e. of 2150latency layers, using the same procedure as described above underExample 1 applied to proper amounts, first of dibasic calcium phosphate,lactose, glyceryl behenate, polyvinylpyrolidone and yellow ferric oxide,and then of colloidal silica, placed in the respective mixer.

Preparation of Buoyant Material

[0082] Buoyant material was prepared, having the following percentagecomposition (by weight): hydrogenated castor oil Cutina HR^((R)), 70.00%from Impag AG, Switzerland magnesium aluminometasilicate NeusilinUFL^((R)), 22.00% from Gustav Parmentier, Germany gelatine from Merck,Germany 5.00% hydrogenated cottonseed oil from Merck, Germany 3.00%Total composition 100.00%

[0083] In the above composition eventually used for preparing thecup-shaped envelope, cf. below, the hydrophobic material is a mixture ofhydrogenated castor oil and hydrogenated cottonseed oil, and the inertpowdered filler is magnesium aluminometasilicate.

[0084] Granulate was prepared in an amount appropriate to allow theproduction of 300 buoyancy conferring cup-hasped envelopes each having aweight of 500.00 mg appropriate to enclose 300 cores so as tomanufacture 300 tablets, using the same procedure as described aboveunder Example 1 applied to proper amounts, first of hydrogenated castoroil and magnesium aluminometasilicate, and then of colloidal silica,placed in the respective mixer.

[0085] 4. Preparation of Cores

[0086] Cores were prepared by means of a single punch machine (typeKorsch, from Korsch Maschinenfabrik, Germany) equipped with dies andcircular flat punches having a diameter of 7.0 mm. The die was filledwith exact quantities of the granulates prepared above, eachcorresponding to the respective layers. The compression step resulted incores having a thickness of 3.90 mm and a hardness of about 50N.

[0087] 5. Application of Buoyancy Conferring Cup-Shaped envelopes ontocores

[0088] The cores previously prepared as described above werepress-coated with the buoyant material prepared as described above,using the same procedure as described above under Example 1. Thecompression step resulted in tablets having a thickness of 7.10 mm and ahardness of about 75N.

[0089] 6. Results

[0090] The in vitro release characteristics of the tablets describedabove were determined, using the same procedure as described above underExample 1 except for monitoring the release of the active substance(diltiazem HCl) by UV spectrophotometry at 240 nm for 5 individualsamples.

[0091] The results are illustrated in FIG. 3 as respective time profilediagrams for the 5 tablet samples. The in vitro release characteristicsof all 5 tablets appeared to form a well grouped family.

[0092] In each instance, the following was observed on the in vitrorelease characteristics:

[0093] The first release of active substance takes place within arelease period of less than a one hour duration.

[0094] The no-release period appears as a well-defined time intervalobserved between the end of the first release and the start of thesecond release, having a duration of more than 4 hours in each instance.

[0095] The second release of active substance takes place within arelease period of less than a one hour duration.

[0096] During the course of the dissolution the tablet system wasmonitored visually and observed to remain buoyant for the whole durationof the experiment, which duration largely exceeded the time required torelease the tablet system's whole content of active substance.

EXAMPLE 3

[0097] 1. Preparation of Active Layers

[0098] Active layers i.e. layers containing active substance wereprepared, using the same procedure as described above under Example 1.

[0099] 2. Preparation of No-Release i.e. Latency Layers

[0100] Latency layers i.e. layers devoid of active substance wereprepared, each having a weight of 100.00 mg and the following percentagecomposition (by weight): dibasic calcium phosphate 43.00% fromEmcompress^((R)), Mendell, USA) lactose (lactose pulvis H2O, 200 Mesh)30.00% Lactose Fast Flo^((R)), from Foremost, USA sodium croscarmelloseAc-Di-Sol^((R)), 2.00% from FMC Corporation, USA glyceryl behenateCompritol^((R)) 888 ATO, 15.00% from Gattefossé, Francepolyvinylpyrrolidone Plasdone^((R)) K29-32, 8.40% from ISP AG,Switzerland yellow ferric oxide Sicovit^((R)) Yellow 10E172, 0.10% fromBascom AG, Switzerland magnesium stearate from Merck, Germany 1.00%colloidal silica Aerosil^((R)) 200, 0.50% from Degussa AG, Hanau,Germany Total composition 100.00%

[0101] Granulate was prepared in an amount appropriate to allow theproduction of 1500 cores of the type described above i.e. of 1500latency layers, using the same procedure as described above underExample 1 applied to proper amounts, first of dibasic calcium phosphate,lactose, sodium croscarmellose, glyceryl behenate, polyvinylpyrolidoneand yellow ferric oxide, and then of magnesium stearate and colloidalsilica, placed in the respective mixer.

[0102] 3. Preparation of Buoyant Material

[0103] Buoyant material was prepared, using the same procedure asdescribed above under Example 1, leading to the same compositioneventually used for preparing the cup-shaped envelope, cf. below, inwhich the hydrophobic material is hydrogenated castor oil and the inertpowdered filler is magnesium aluminometasilicate.

4. Preparation of Cores

[0104] Cores were prepared, using the same procedure as described aboveunder Example 2, to result in cores having a thickness of 4.25 mm and ahardness of about 50N.

[0105] 5. Application of Buoyancy Conferring Cup-Shaped Envelopes OntoCores

[0106] The cores previously prepared as described above werepress-coated with the buoyant material prepared as described above,using the same procedure as described above under Example 1. Thecompression step resulted in tablets having a thickness of 7.05 mm and ahardness of about 105N.

[0107] 6. Results

[0108] The in vitro release characteristics of the tablets describedabove were determined, using the same procedure as described above underExample 2 except for monitoring the release of the active substance(diltiazem HCl) for 6 individual samples.

[0109] The results are illustrated in FIG. 4 as respective time profilediagrams for the 6 tablet samples. The in vitro release characteristicsof all 6 tablets appeared to form a well grouped family.

[0110] In each instance, the following was observed on the in vitrorelease characteristics:

[0111] The first release of active substance takes place within arelease period of less than a one hour duration.

[0112] The no-release period appears as a well-defined time intervalobserved between the end of the first release and the start of thesecond release, having a duration of more than 2 hours in each instance.

[0113] The second release of active substance takes place within arelease period of less than a one hour duration.

[0114] During the course of the dissolution the tablet system wasmonitored visually and observed to remain buoyant for the whole durationof the experiment, which duration largely exceeded the time required torelease the tablet system's whole content of active substance.

SUMMARY OF EXPERIMENTAL RESULTS

[0115] In each instance of the Examples, in the composition eventuallyused for preparing the cup-shaped envelope the inert powdered filler ismagnesium aluminometasilicate and the hydrophobic material ishydrogenated castor oil (in Example 1 and Example 3) or a mixture ofhydrogenated castor oil and hydrogenated cottonseed oil (in Example 2).

[0116] In each instance and for all three Examples, the first release ofactive substance takes place within a release period of less than a onehour duration.

[0117] In each instance, the no-release period appears to be awell-defined time interval observed between the end of the first releaseand the start of the second release, having a duration of more than 8hours in each instance of Example 1, 4 hours in each instance of Example2, and 2 hours in each instance of Example 3.

[0118] In each instance, the second release of active substance isobserved to produce a controlled release having a prolonged duration(sustained release) in each instance of Example 1, and in contrast aduration of less than one hour in each instance of Example 2 and Example3.

[0119] During the course of the dissolution the tablet system wasmonitored visually and observed to remain buoyant for the whole durationof the experiment, which duration largely exceeded the time required torelease the tablet system's whole content of active substance in eachinstance of Example 2 and Example 3.

1. A pharmaceutical tablet system capable of prolonged floating in or ongastric fluid for releasing therein one or more pharmaceutically activesubstances in the course of an alternate succession of periods ofsubstance release and no-release, said alternate succession including atleast two periods of substance release separated by one period ofno-release, whereby the tablet system is made up of a multilayered coreplaced in a cup-shaped envelope, the core is made up of release andno-release layers superposed in alternate succession to form a pile oflayers that includes at least two release layers flanking anintermediate no-release layer, each release layer being composed ofpharmaceutically acceptable excipient and/or carrier having admixedthereto at least one of said pharmaceutically active substances, eachno-release layer being composed of pharmaceutically acceptable excipientand/or carrier devoid of said pharmaceutically active substance, thecup-shaped envelope covers a bottom surface and side surfaces of thecore placed therein while leaving exposed an upper surface of the core,characterized in that the cup-shaped envelope provides for buoyancy ofthe pharmaceutical tablet system with respect to gastric fluid by beingformed of a compression-sintered mixture that comprises pharmaceuticallyacceptable hydrophobic material and pharmaceutically acceptable inertpowdered filler, the hydrophobic material being composed of fatty and/orwaxy material capable of being sintered by compression and whose bulkdensity is lower than gastric fluid density, and the powdered fillerhaving a loose powder density that is lower than gastric fluid density.2. A pharmaceutical tablet system according to claim 1, in which thevoids are interstices between grains of the powdered filler.
 3. Apharmaceutical tablet system according to claim 2, in which the voidsgenerally are sealed off from each other by virtue of the hydrophobicmaterial.
 4. A pharmaceutical tablet system according to claim 1, inwhich the voids are micropores included within the hydrophobic material.5. A pharmaceutical tablet system according to claim 1, in which themixture which the cup-shaped envelope is made of also includes at leastone or more pharmaceutically active agent different from said substancescontained in one or more release layers.
 6. A process of producing apharmaceutical tablet system according to claim 1, involving thefollowing steps: coating the powdered filler with the hydrophobicmaterial; granulating the resulting coated material; placing a layer ofthe resulting granulated material into a die; placing a core accordingto claim 1 onto the layer of granulated material within the die; forcingthe core into the layer of granulated material within the die; andremoving the resulting tablet system from the die.
 7. A processaccording to claim 6, in which the step of forcing the core into thelayer of granulated material within the die involves a compression ofthe tablet system made up of the cup-shaped envelope having the coreinserted therein to provide a snug fit between mutually facing bottomand side surfaces of the core and surface portions of the cup-shapedenvelope.
 8. A process of producing a cup-shaped envelope of apharmaceutical tablet system according to claim 1, involving thefollowing steps: coating the powdered filler with the hydrophobicmaterial; granulating the resulting coated material; placing a layer ofthe resulting granulated material into a die; forming a cup-shapedrecess into the layer of granulated material by forcing acorrespondingly shaped body into it within the die; and removing theresulting cup-shaped envelope from the die.
 9. A process according toany of claims 6 to 8, in which the step of coating the powdered fillerwith the hydrophobic material is a step of spray-coating performed undervigorous stirring.